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This Month in AJP

    Open AccessPublished:June 27, 2011DOI:https://doi.org/10.1016/j.ajpath.2011.05.030

        Seeing Deeper Leads to Deeper Understanding

        The early detection of internal organ disease is critical to accurate diagnosis, management, or cure. Magnetic resonance (MR) imaging has aided the transformation of diagnosis in vivo; however, this technology is limited by low resolution. Grippo et al (Am J Pathol 2011, 179:610–618) used high-field-strength MR without contrast agents to visualize acini, islets, and blood vessels of ex vivo murine pancreata. High-field-strength MR results corresponded well with established criteria obtained by histology and the compiling of 2D images into a 3D image set. Such improvements to imaging technology may, in the future, lead to more accurate diagnoses and treatment.

        A New Model for Testing Pulmonary Disease

        Obliterative bronchiolitis is a life-threatening disease that may develop subsequent to lung transplantation. A new report by Xue et al (Am J Pathol 2011, 179:745–753) describes development and validation of a model that utilizes both human lung tissue and human effector cells. Lung explants from human cadavers were transplanted into NOD/SCID mice, followed by adoptive transfer of allogeneic human T cells. Three weeks after implantation, the lung tissue showed evidence of inflammatory cell infiltration, and one week later, tissue exhibited extensive damage (ie, loss of airway epithelium and obliteration of airway lumens). This model provides a promising opportunity to evaluate the ability of immunosuppressants to delay the onset of disease.

        Activating Different TLRs Produces Different Outcomes in the Brain

        The Toll-like receptors (TLRs) are active in the innate immune response, and each recognizes a different, specific component of bacteria or viruses. Whereas TLR7 recognizes single-strand RNA (and the agonist imiquimod) and TLR9 binds to oligonucleotides lacking methylation at CpG sites (CpG-ODN), both receptors share signaling pathway components. Butchi et al (Am J Pathol 2011, 179:783–794) examined the ability of TLR7 and TLR9 agonists to mediate neuroinflammation. Imiquimod-activated TLR7 elicited a weak inflammatory response compared to that of CpG-ODN-mediated TLR9, which effected significantly larger releases of cytokines (ie, IL-12 p40 and tumor necrosis factor) and a breakdown of the blood-CSF barrier, leading to infiltration of the CNS by peripheral cells. Choroid plexus cells are surmised to broker the increase in cytokine production brought on by TLR9 activation. These findings indicate that proper drug choice, insofar as TLR responses are concerned, is critical to ameliorating neuroinflammation.

        Follistatin Improves Skeletal Muscle Healing

        Fibrosis and inadequate myofiber regeneration frequently hamper recovery from skeletal muscle injury. In an effort to identify therapies that both stimulate muscle regeneration and inhibit fibrosis, Zhu et al (Am J Pathol 2011, 179:915–930) investigated follistatin, an antagonist of the TGF-β superfamily member myostatin. After skeletal muscle injury, follistatin-overexpressing transgenic mice displayed significantly greater myofiber regeneration and less fibrosis formation compared to wild-type mice. Furthermore, isolated muscle progenitor cells showed improved regeneration of dystrophin-positive myofibers when transplanted into the skeletal muscle of mdx/SCID mice. In vitro, follistatin stimulated myoblasts to express the myogenic transcription factors MyoD, Myf5, and myogenin. Thus, follistatin may be beneficial for a variety of skeletal muscle injuries and disorders, such as muscular dystrophies.

        Cutting the Effect of Fat in Breast Cancer

        Obesity conveys significant risk for breast cancer, and the adipocyte-expressed cytokine leptin plays a crucial role. Catalano et al (Am J Pathol 2011, 179:1030–1040) evaluated the ability of peroxisome proliferator-activated receptor-gamma (PPARγ) ligands to counteract leptin stimulatory effects on breast cancer growth. PPARγ activation prevented the development of leptin-induced MCF-7 tumor xenografts in mice and inhibited cell-cell aggregation and proliferation. PPARγ ligands also abrogated upregulated gene expression of leptin and its receptors, inhibited leptin signaling mediated by MAPK/STAT3/Akt phosphorylation, and counteracted leptin's stimulatory effects on estrogen signaling. These results highlight the possible therapeutic benefits of PPARγ ligands in the treatment of breast cancer.

        Linked Article

        • Visualization of Mouse Pancreas Architecture Using MR Microscopy
          The American Journal of PathologyVol. 179Issue 2
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            Pancreatic diseases, which include diabetes, pancreatitis, and pancreatic cancer, are often difficult to detect and/or stage, contributing to a reduced quality of life and lifespan for patients. Thus, there is need for a technology that can visualize tissue changes in the pancreas, improve understanding of disease progression, and facilitate earlier detection in the human population. Because of low spatial resolution, current clinical magnetic resonance imaging (MRI) at low field strength has yet to fully visualize the exocrine, endocrine, vascular, and stromal components of the pancreas.
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        • TLR7 and TLR9 Trigger Distinct Neuroinflammatory Responses in the CNS
          The American Journal of PathologyVol. 179Issue 2
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            Toll-like receptors (TLRs) 7 and 9 recognize nucleic acid determinants from viruses and bacteria and elicit the production of type I interferons and proinflammatory cytokines. TLR7 and TLR9 are similar regarding localization and signal transduction mechanisms. However, stimulation of these receptors has differing effects in modulating viral pathogenesis and in direct toxicity in the central nervous system (CNS). In the present study, we examined the potential of the TLR7 agonist imiquimod and the TLR9 agonist cytosine-phosphate-guanosine oligodeoxynucleotide (CpG-ODN) to induce neuroinflammation after intracerebroventricular inoculation.
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        • Follistatin Improves Skeletal Muscle Healing after Injury and Disease through an Interaction with Muscle Regeneration, Angiogenesis, and Fibrosis
          The American Journal of PathologyVol. 179Issue 2
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            Recovery from skeletal muscle injury is often incomplete because of the formation of fibrosis and inadequate myofiber regeneration; therefore, injured muscle could benefit significantly from therapies that both stimulate muscle regeneration and inhibit fibrosis. To this end, we focused on blocking myostatin, a member of the transforming growth factor–β superfamily and a negative regulator of muscle regeneration, with the myostatin antagonist follistatin. In vivo, follistatin-overexpressing transgenic mice underwent significantly greater myofiber regeneration and had less fibrosis formation compared with wild-type mice after skeletal muscle injury.
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        • A Human-Mouse Chimeric Model of Obliterative Bronchiolitis after Lung Transplantation
          The American Journal of PathologyVol. 179Issue 2
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            Obliterative bronchiolitis is a frequent, morbid, and usually refractory complication of lung transplantation. Mechanistic study of obliterative bronchiolitis would be aided by development of a relevant model that uses human immune effector cells and airway targets. Our objective was to develop a murine chimera model that mimics obliterative bronchiolitis of lung allograft recipients in human airways in vivo. Human peripheral blood mononuclear cells were adoptively transferred to immunodeficient mice lacking activity of T, B, and NK cells, with and without concurrent transplantations of human small airways dissected from allogeneic cadaveric lungs.
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        • In Vivo and in Vitro Evidence That PPARγ Ligands Are Antagonists of Leptin Signaling in Breast Cancer
          The American Journal of PathologyVol. 179Issue 2
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            Obesity is a major risk factor for the development and progression of breast cancer. Leptin, a cytokine mainly produced by adipocytes, plays a crucial role in mammary carcinogenesis and is elevated in hyperinsulinemia and insulin resistance. The antidiabetic thiazolidinediones inhibit leptin gene expression through ligand activation of the peroxisome proliferator-activated receptor-γ (PPARγ) and exert antiproliferative and apoptotic effects on breast carcinoma. In this study, we investigated the ability of PPARγ ligands to counteract leptin stimulatory effects on breast cancer growth in either in vivo or in vitro models.
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